Brucine Suppresses Malignant Progression of Prostate Cancer by Decreasing Sarcosine Accumulation via Downregulation of GNMT in the Glycine/sarcosine Metabolic Pathway.
Amino acid metabolism
Apoptosis
Brucine
Proliferation
Prostate cancer
Journal
Cell biochemistry and biophysics
ISSN: 1559-0283
Titre abrégé: Cell Biochem Biophys
Pays: United States
ID NLM: 9701934
Informations de publication
Date de publication:
14 Jun 2024
14 Jun 2024
Historique:
accepted:
01
06
2024
medline:
15
6
2024
pubmed:
15
6
2024
entrez:
14
6
2024
Statut:
aheadofprint
Résumé
Prostate cancer (PCa) remains a leading cause of cancer-related incidence and mortality in men. Disruptions in amino acid (AA) metabolism contribute to the disease progression, with brucine, a glycine antagonist, exhibiting antitumor effects. This study explores the antitumor impact of brucine on PCa and investigates its mechanisms in regulating AA metabolic pathways. The study employed the PCa cell line DU-145, characterized by high sarcosine (Sar) levels, for various assays including Cell Counting Kit-8 (CCK8), wound healing, Transwell, 5-Ethynyl-2'-deoxyuridine (EDU), TdT mediated dUTP Nick End Labeling (TUNEL), flow cytometry, Western blot, and ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Network pharmacological analysis determined the anticancer mechanisms of brucine. Sar levels in DU-145 cells were significantly higher than in normal prostatic epithelial cells RWPE-1. Treatment with brucine resulted in a marked decrease in cell viability, proliferation, invasion, and migration, while promoting apoptosis in a dose-dependent manner. Sar levels decreased with increasing brucine concentration. Network pharmacology analysis linked brucine's anticancer effect to the AA metabolism and glycine N-methyltransferase (GNMT) pathways. GNMT expression in prostate cancer tissues and The Cancer Genome Atlas database was significantly elevated compared to controls. Treatment with brucine led to downregulation of GNMT expression in DU-145 cells without significant effect on sarcosine dehydrogenase (SARDH). Addition of recombinant GNMT partially reversed the inhibitory effects of brucine on DU-145 cells. Treatment with brucine downregulates GNMT expression in DU-145 cells, reducing Sar accumulation and inhibiting tumor progression. These findings provide new insights into the antitumor mechanisms of brucine in PCa.
Identifiants
pubmed: 38877335
doi: 10.1007/s12013-024-01348-z
pii: 10.1007/s12013-024-01348-z
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : the Science and Technology Planning Project of Traditional Chinese Medicine, Jiangsu
ID : YB2020050
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Références
Saeidi, H., Ismail, P., & Samudi Raju, C., et al. (2023). Genetic alterations in prostate cancer as diagnostic and prognostic markers. Malaysian Journal of Pathology, 45(2), 149–155.
pubmed: 37658525
Washington, C., Goldstein, D. A., & Moore, A., et al. (2022). Health Disparities in Prostate Cancer and Approaches to Advance Equitable Care. American Society of Clinical Oncology Educational Book, 42, 1–6.
pubmed: 35671436
Liu, J., Dong, L., & Zhu, Y., et al. (2022). Prostate cancer treatment - China’s perspective. Cancer Letters, 550, 215927.
doi: 10.1016/j.canlet.2022.215927
pubmed: 36162714
Sung, H., Ferlay, J., & Siegel, R. L., et al. (2021). Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA A Cancer Journal for Clinicians, 71(3), 209–249.
doi: 10.3322/caac.21660
pubmed: 33538338
Wang, G., Zhao, D., & Spring, D. J., et al. (2018). Genetics and biology of prostate cancer. Genes Dev, 32(17-18), 1105–1140.
doi: 10.1101/gad.315739.118
pubmed: 30181359
pmcid: 6120714
Harris, A. E., Metzler, V. M., & Lothion-Roy, J., et al. (2022). Exploring anti-androgen therapies in hormone dependent prostate cancer and new therapeutic routes for castration resistant prostate cancer. Frontiers in Endocrinology, 13, 1006101.
doi: 10.3389/fendo.2022.1006101
pubmed: 36263323
pmcid: 9575553
Zhang, Q., Zhang, P., & Zhao, Z., et al. (2023). Exploring the role of differentially expressed metabolic genes and their mechanisms in bone metastatic prostate cancer. PeerJ, 11, e15013.
doi: 10.7717/peerj.15013
pubmed: 37070095
pmcid: 10105558
Zhang, X., Xia, B., & Zheng, H., et al. (2022). Identification of characteristic metabolic panels for different stages of prostate cancer by (1)H NMR-based metabolomics analysis. Journal of Translational Medicine, 20(1), 275.
doi: 10.1186/s12967-022-03478-5
pubmed: 35715864
pmcid: 9205125
Kdadra, M., Hockner, S., & Leung, H., et al. (2019). Metabolomics Biomarkers of Prostate Cancer: A Systematic Review. Diagnostics, 9(1), 21.
doi: 10.3390/diagnostics9010021
pubmed: 30791464
pmcid: 6468767
Zheng, H., Dong, B., & Ning, J., et al. (2020). NMR-based metabolomics analysis identifies discriminatory metabolic disturbances in tissue and biofluid samples for progressive prostate cancer. Clinica Chimica Acta, 501, 241–251.
doi: 10.1016/j.cca.2019.10.046
Strmiska, V., Michalek, P., & Eckschlager, T., et al. (2019). Prostate cancer-specific hallmarks of amino acids metabolism: Towards a paradigm of precision medicine. Biochimica et Biophysica Acta Reviews on Cancer, 1871(2), 248–258.
doi: 10.1016/j.bbcan.2019.01.001
pubmed: 30708041
Sreekumar, A., Poisson, L. M., & Rajendiran, T. M., et al. (2009). Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature, 457(7231), 910–4.
doi: 10.1038/nature07762
pubmed: 19212411
pmcid: 2724746
Huang, Y. C., Lee, C. M., & Chen, M., et al. (2007). Haplotypes, loss of heterozygosity, and expression levels of glycine N-methyltransferase in prostate cancer. Clinical Cancer Research, 13(5), 1412–20.
doi: 10.1158/1078-0432.CCR-06-1551
pubmed: 17332283
Dodt, G., Kim, D. G., & Reimann, S. A., et al. (2000). L-Pipecolic acid oxidase, a human enzyme essential for the degradation of L-pipecolic acid, is most similar to the monomeric sarcosine oxidases. Biochemical Journal, 345(Pt 3), 487–94.
doi: 10.1042/bj3450487
pubmed: 10642506
pmcid: 1220782
Song, Y. H., Shiota, M., & Kuroiwa, K., et al. (2011). The important role of glycine N-methyltransferase in the carcinogenesis and progression of prostate cancer. Modern Pathology, 24(9), 1272–80.
doi: 10.1038/modpathol.2011.76
pubmed: 21572396
Strmiska, V., Michalek, P., & Lackova, Z., et al. (2019). Sarcosine is a prostate epigenetic modifier that elicits aberrant methylation patterns through the SAMe-Dnmts axis. Molecular Oncology, 13(5), 1002–1017.
Khan, A. P., Rajendiran, T. M., & Ateeq, B., et al. (2013). The role of sarcosine metabolism in prostate cancer progression. Neoplasia, 15(5), 491–501.
doi: 10.1593/neo.13314
pubmed: 23633921
pmcid: 3638352
Heger, Z., Gumulec, J., & Cernei, N., et al. (2016). Relation of exposure to amino acids involved in sarcosine metabolic pathway on behavior of non-tumor and malignant prostatic cell lines. Prostate, 76(7), 679–90.
doi: 10.1002/pros.23159
pubmed: 26847870
Lu, L., Huang, R., & Wu, Y., et al. (2020). Brucine: A Review of Phytochemistry, Pharmacology, and Toxicology. Frontiers in Pharmacology, 11, 377.
doi: 10.3389/fphar.2020.00377
pubmed: 32308621
pmcid: 7145893
Kang, Q., Zheng, K., & Jiang, G. M., et al. (2023). Brucine suppresses proliferation and promotes apoptosis of human cholangiacarcinoma cells via the inhibition of COX2 expression. Journal of Cancer, 14(14), 2700–2706.
doi: 10.7150/jca.87514
pubmed: 37779869
pmcid: 10539398
Lei, Y., Hou, F., & Wu, X., et al. (2022). Brucine-Induced Neurotoxicity by Targeting Caspase 3: Involvement of PPARgamma/NF-kappaB/Apoptosis Signaling Pathway. Neurotoxicity Research, 40(6), 2117–2131.
Yan, W., Zeng, Z., & Qin, F., et al. (2022). Effects of brucine on mitochondrial apoptosis and expression of HSP70 in prostate cancer cells. Translational Cancer Research, 11(3), 500–507.
doi: 10.21037/tcr-22-209
pubmed: 35402184
pmcid: 8990831
Liu, X., Yu, C., & Bi, Y., et al. (2019). Trends and age-period-cohort effect on incidence and mortality of prostate cancer from 1990 to 2017 in China. Public Health, 172, 70–80.
doi: 10.1016/j.puhe.2019.04.016
pubmed: 31220754
Shen, M. M., & Abate-Shen, C. (2010). Molecular genetics of prostate cancer: new prospects for old challenges. Genes and Development, 24(18), 1967–2000.
doi: 10.1101/gad.1965810
pubmed: 20844012
pmcid: 2939361
Huggins, C., & Hodges, C. V. (2002). Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. The Journal of Urology, 167(2 Pt 2), 948–51. discussion 952.
doi: 10.1016/S0022-5347(02)80307-X
pubmed: 11905923
Chen, X., Overcash, R., & Green, T., et al. (2011). The tumor suppressor activity of the transmembrane protein with epidermal growth factor and two follistatin motifs 2 (TMEFF2) correlates with its ability to modulate sarcosine levels. Journal of Biological Chemistry, 286(18), 16091–100.
doi: 10.1074/jbc.M110.193805
pubmed: 21393249
pmcid: 3091218
Yang, Y., Li, P., & Li, X., et al. (2024). Brucine D restrains colorectal cancer tumorigenesis and autophagy by downregulating circ_0068464. Chemical Biology and Drug Design, 103(1), e14407.
doi: 10.1111/cbdd.14407
pubmed: 38040413
Li, M., Li, P., & Zhang, M., et al. (2018). Brucine suppresses breast cancer metastasis via inhibiting epithelial mesenchymal transition and matrix metalloproteinases expressions. Chinese Journal of Integrative Medicine, 24(1), 40–46.
doi: 10.1007/s11655-017-2805-1
pubmed: 28795388
Shu, G., Mi, X., & Cai, J., et al. (2013). Brucine, an alkaloid from seeds of Strychnos nux-vomica Linn., represses hepatocellular carcinoma cell migration and metastasis: the role of hypoxia inducible factor 1 pathway. Toxicology Letters, 222(2), 91–101.
doi: 10.1016/j.toxlet.2013.07.024
pubmed: 23933019
Seshadri, V. D. (2021). Brucine promotes apoptosis in cervical cancer cells (ME-180) via suppression of inflammation and cell proliferation by regulating PI3K/AKT/mTOR signaling pathway. Environmental Toxicology, 36(9), 1841–1847.
doi: 10.1002/tox.23304
pubmed: 34076332
Shi, X., Zhu, M., & Kang, Y., et al. (2018). Wnt/beta-catenin signaling pathway is involved in regulating the migration by an effective natural compound brucine in LoVo cells. Phytomedicine, 46, 85–92.
doi: 10.1016/j.phymed.2018.04.019
pubmed: 30097126
Matos, A., Carvalho, M., & Bicho, M., et al. (2021). Arginine and Arginases Modulate Metabolism, Tumor Microenvironment and Prostate Cancer Progression. Nutrients, 13(12), 4503.
doi: 10.3390/nu13124503
pubmed: 34960055
pmcid: 8704013
Gao, X., Locasale, J. W., & Reid, M. A. (2019). Serine and Methionine Metabolism: Vulnerabilities in Lethal Prostate Cancer. Cancer Cell, 35(3), 339–341.
doi: 10.1016/j.ccell.2019.02.014
pubmed: 30889375
pmcid: 6425948
Chen, L., Xu, Y. X., & Wang, Y. S., et al. (2023). Lipid metabolism, amino acid metabolism, and prostate cancer: a crucial metabolic journey. Asian Journal of Andrology, 26(2), 123–34.
doi: 10.4103/aja202363
pubmed: 38157428
pmcid: 10919422
Pal, S., Sharma, A., & Mathew, S. P., et al. (2022). Targeting cancer-specific metabolic pathways for developing novel cancer therapeutics. Frontiers in Immunology, 13, 955476.
doi: 10.3389/fimmu.2022.955476
pubmed: 36618350
pmcid: 9815821
Cavaliere, B., Macchione, B., & Monteleone, M., et al. (2011). Sarcosine as a marker in prostate cancer progression: a rapid and simple method for its quantification in human urine by solid-phase microextraction-gas chromatography-triple quadrupole mass spectrometry. Analytical and Bioanalytical Chemistry, 400(9), 2903–12.
doi: 10.1007/s00216-011-4960-0
pubmed: 21491110
Lasorsa, F., di Meo, N. A., & Rutigliano, M., et al. (2023). Emerging Hallmarks of Metabolic Reprogramming in Prostate Cancer. International Journal of Molecular Sciences, 24(2), 910.
doi: 10.3390/ijms24020910
pubmed: 36674430
pmcid: 9863674